Clinical trials that used HMB for the treatment of muscle wasting have involved the administration of 3 grams of HMB per day under different dosing regimens.[16] According to one review, an optimal dosing regimen is to administer it in one 1 gram dose, three times a day, since this ensures elevated plasma concentrations of HMB throughout the day;[16] however, as of June 2016 the best dosing regimen for muscle wasting conditions is still being investigated.[20]

Some branded products that contain HMB (i.e., certain formulations of Ensure and Juven) are medical foods that are intended to be used to provide nutritional support under the care of a doctor in individuals with muscle wasting due to HIV/AIDS or cancer, to promote wound healing following surgery or injury, or when otherwise recommended by a medical professional.[sources 3] Juven, a nutrition product which contains 3 grams of HMB-Ca, 14 grams of L-arginine, and 14 grams of L-glutamine per two servings,[2] has been shown to improve lean body mass during clinical trials in individuals with AIDS and cancer, but not rheumatoid cachexia.[17][34][35] Further research involving the treatment of cancer cachexia with Juven over a period of several months is required to adequately determine treatment efficacy.[17][34]

Enhancing performance

With an appropriate exercise program, dietary supplementation with 3 grams of HMB per day has been shown to increase exercise-induced gains in muscle size, muscle strength and power, and lean body mass, reduce exercise-induced skeletal muscle damage,[note 3] and expedite recovery from high-intensity exercise.[sources 2] Based upon limited clinical research, HMB supplementation may also improve aerobic exercise performance and increase gains in aerobic fitness when combined with high-intensity interval training.[12][14] These effects of HMB are more pronounced in untrained individuals and athletes who perform high intensity resistance or aerobic exercise.[1][12][14] In resistance-trained populations, the effects of HMB on muscle strength and lean body mass are limited.[38] HMB effects muscle size, strength, mass, power, and recovery in part by stimulating myofibrillar muscle protein synthesis and inhibiting muscle protein breakdown through various mechanisms, including the activation of mechanistic target of rapamycin complex 1 (mTORC1) and inhibition of proteasome-mediated proteolysis in skeletal muscles.[14][15]

The efficacy of HMB supplementation for reducing skeletal muscle damage from prolonged or high-intensity exercise is affected by the time that it is used relative to exercise.[1][37] The greatest reduction in skeletal muscle damage from a single bout of exercise has been shown to occur when HMB-Ca is ingested 1–2 hours prior to exercise or HMB-FA is ingested 30–60 minutes prior to exercise.[1]

Two animal studies have examined the effects of HMB supplementation in pregnant pigs on the offspring and reported no adverse effects on the fetus.[26] No clinical testing with supplemental HMB has been conducted on pregnant women,[39] and pregnant and lactating women are advised not to take HMB by Metabolic Technologies, Inc., the company that grants licenses to include HMB in dietary supplements, due to a lack of safety studies.[39]

As of May 2016, the signaling cascade that mediates the HMB-induced reduction in muscle protein breakdown has not been identified in living humans, although it is well-established that it attenuates proteolysis in humans in vivo.[11][15] Unlike L-leucine, HMB attenuates muscle protein breakdown in an insulin-independent manner in humans.[note 6][15] HMB is believed to reduce muscle protein breakdown in humans by inhibiting the 19S and 20S subunits of the ubiquitin–proteasome system in skeletal muscle and by inhibiting apoptosis of skeletal muscle nuclei via unidentified mechanisms.[15][16][42]

Based upon animal studies, HMB appears to be metabolized within skeletal muscle into cholesterol, which may then be incorporated into the muscle cell membrane, thereby enhancing membrane integrity and function.[35][36] The effects of HMB on muscle protein metabolism may help stabilize muscle cell structure.[26] One review suggested that the observed HMB-induced reduction in the plasma concentration of muscle damage biomarkers (i.e., muscle enzymes such as creatine kinase and lactate dehydrogenase) in humans following intense exercise may be due to a cholesterol-mediated improvement in muscle cell membrane function.[note 3][26]

Pharmacokinetics

This graph shows the plasma concentration of HMB (in units of micromoles per liter of blood plasma) over time following ingestion of a 1 gram dose of the calcium or free acid form of HMB.[1]

The free acid (HMB-FA) and monohydrated calcium salt (HMB-Ca) forms of HMB have different pharmacokinetics.[1][23] HMB-FA is more readily absorbed into the bloodstream and has a longer elimination half-life (3 hours) relative to HMB-Ca (2.5 hours).[1][23] Tissue uptake and utilization of HMB-FA is 25–40% higher than for HMB-Ca.[1][23] The fraction of an ingested dose that is excreted in urine does not differ between the two forms.[1]

After ingestion, HMB-Ca is converted to β-hydroxy β-methylbutyrate following dissociation of the calcium moiety in the gut.[1] When the HMB-Ca dosage form is ingested, the magnitude and time at which the peak plasma concentration of HMB occurs depends on the dose and concurrent food intake.[1] Higher HMB-Ca doses increase the rate of absorption, resulting in a peak plasma HMB level (Cmax) that is disproportionately greater than expected of a linear dose-response relationship and which occurs sooner relative to lower doses.[note 7][1] Consumption of HMB-Ca with sugary substances slows the rate of HMB absorption, resulting in a lower peak plasma HMB level that occurs later.[note 7][1]

HMB is eliminated via the kidneys, with roughly 10–40% of an ingested dose being excreted unchanged in urine.[1][3] The remaining 60–90% of the dose is retained in tissues or excreted as HMB metabolites.[1][3] The fraction of a given dose of HMB that is excreted unchanged in urine increases with the dose.[note 8][1]

in 1880 and 1889, Schirokoff and Reformatsky (respectively) reported that the oxidative cleavage of the vicinal diol 4-methylpentane-1,2,4-triol with acidified potassium permanganate (KMnO4) yields HMB[56][57] – this result is closest related to the first synthesis as cold dilute KMnO4 oxidises alkenes to vicinal cis-diols which hot acid KMnO4 further oxidises to carbonyl-containing compounds, and the diol intermediate is not obtained when hot acidic conditions are used for alkene oxidation.[58] In other words, racemic 4-methylpentane-1,2,4-triol is a derivative of 2-methylpent-4-en-2-ol and β-hydroxy β-methylbutyric acid is a derivative of both; and,

in 1892, Kondakow reported the preparation of HMB by permanganate oxidation of 3-methylbutane-1,3-diol.[59]

In a study where participants consumed 2.42 grams of pure HMB-FA while fasting, the average plasma HMB concentration increased from a basal level of 5.1 μM to 408 μM after 30 minutes.[15] At 150 minutes post-ingestion, the average plasma HMB concentration among participants was 275 μM.[15]

Abnormal HMB concentrations in urine and blood plasma have been noted in several disease states where it may serve as a diagnostic biomarker, particularly in the case of metabolic disorders.[50] The following table lists some of these disorders along with the associated HMB concentrations detected in urine or blood plasma.[50]

The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s.[8][27] Nissen founded a company called Metabolic Technologies, Inc. (MTI) around the time of his discovery, which later acquired six HMB-related patents that the company has used to license the right to manufacture and incorporate HMB into dietary supplements.[27][70][71] When it first became available commercially in the late 1990s, HMB was marketed solely as an exercise supplement to help athletes and bodybuilders build muscle.[70] MTI subsequently developed two HMB-containing products, Juven and Revigor, to which Abbott Nutrition obtained the market rights in 2003 and 2008 respectively.[8][70] Since then, Abbott has marketed Juven as a medical food and the Revigor brand of HMB as an active ingredient in food products for athletes (e.g., certain formulations of Myoplex) and other medical foods (e.g., certain formulations of Ensure).[8][24][70]

Notes

^ abThe meta-analysis found that the average increase in muscle mass due to HMB supplementation in older adults was 0.35 kilograms (0.77 lb).[11] The 95% confidence interval for the estimated increase in muscle mass due to HMB supplementation is 0.11–0.59 kilograms (0.24–1.30 lb).[11]The seven randomized controlled trials that were included in the meta-analysis contained a total of 147 older adults in the HMB treatment groups and 140 older adults in the control groups.[11] The seven trials had durations of 2–11 months and the average duration of the studies, weighted by their sample size, was approximately 6 months.[11]

^The NOAEL was established based upon a 3-month study involving several groups of Sprague-Dawley rats that were administered different daily doses of HMB-FA.[18][26] No adverse effects were observed in any group that received HMB, so the highest daily dose of HMB that was administered in this study was identified as the NOAEL.[18][26]

^Approximately equal doses of pure HMB-FA (2.42 grams) and L-leucine (3.42 grams) do not produce statistically distinguishable anabolic effects, as measured by the fractional synthesis of myofibrillar proteins, in the skeletal muscle of living humans.[15][41] At 150 minutes post-ingestion, these doses of HMB-FA and L-leucine increased muscle protein synthesis by ~70% and ~110% respectively in one study.[15][41]

^At 150 minutes post-ingestion, a 2.42 gram dose of pure HMB-FA decreased skeletal muscle protein breakdown in living humans by 57% in one study.[15][41] The effect of L-leucine on muscle protein breakdown is entirely dependent upon insulin secretion and consequently was not measured in the same study.[15] By comparison, the insulin-dependent reduction in muscle protein breakdown following an entire meal that contains L-leucine and carbohydrates is ~50% on average.[15]

^ abIn one study, ingestion of a 1 gram dose of HMB-Ca by healthy volunteers produced a peak plasma HMB level of 120 μM at 2 hours following ingestion, while ingestion of a 3 gram dose of HMB-Ca produced a peak plasma HMB level of 487 μM at 1 hour following ingestion.[1] Consumption of 3 grams of HMB-Ca with 75 grams of glucose resulted in a lower peak plasma HMB level of 352 μM which occurred later at 2 hours following ingestion.[1]

^In one study, ingestion of a 1 gram and 3 gram HMB dose resulted in the excretion of 14% and 28% of the dose as HMB in urine, respectively.[1]

^ abcdefghijklmZanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). “HMB supplementation: clinical and athletic performance-related effects and mechanisms of action”. Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID20607321. HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).

^“beta-Hydroxyisovaleric acid”. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 3 February 2018. Archived from the original on 6 February 2018. Retrieved 6 February 2018. Chemical Names: Beta-Hydroxyisovaleric acid; 3-Hydroxy-3-methylbutanoic acid; … 3-Hydroxyisovaleric acid; 3-Hydroxy-3-methylbutyric acid

^ abcdefghLinn J (13 May 2013). “Proteins in Human Health and Performance”. Iowa State University. Archived from the original on 27 August 2016. Retrieved 31 July 2016. Dr. Nissen and his collaborator Dr. Naji N. Abumrad, Professor and Chair, Department of Surgery, Vanderbilt University, discovered beta-hydroxy-beta-methylbutyrate (HMB) and its beneficial effects on human health and performance. HMB is currently marketed nationally by Abbott Laboratories as Revigor™, which is a component of Ensure® Muscle Health, and Juven®, which is a nutritional beverage that is clinically shown to promote healing after injury or surgery.

^ abcdefHoleček M (August 2017). “Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions”. Journal of Cachexia, Sarcopenia and Muscle. 8 (4): 529–541. doi:10.1002/jcsm.12208. PMC5566641. PMID28493406. The reports summarized here indicate that HMB provides a number of benefits to subjects involved in strength-power and endurance sports. The effects on muscle mass and strength, particularly during resistance training, are likely related to the suppression of proteolysis and a positive effect on protein synthesis. Its benefits in aerobic performance are probably more associated with improved mitochondrial biogenesis and fat oxidation. Favourable effects on the recovery from exercise-induced damage may be related to the role of HMB as a precursor of cholesterol, which modulates membrane fluidity and affects ion channels, and membrane excitability. … Studies have demonstrated that HMB can prevent the development of sarcopenia in elderly subjects and that the optimal action of HMB on muscle growth and strength occurs when it is combined with exercise.

^ abRossi AP, D’Introno A, Rubele S, Caliari C, Gattazzo S, Zoico E, Mazzali G, Fantin F, Zamboni M (October 2017). “The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity”. Drugs & Aging. 34 (11): 833–840. doi:10.1007/s40266-017-0496-0. PMID29086232. Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects. HMB supplementation results in an increase in skeletal muscle mass and strength in the elderly and its effect is even greater when combined with physical exercise.

^ abcdefghijklmnopWilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). “Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism”. The Journal of Physiology. 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC3690694. PMID23551944. The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008). … Furthermore, there was clear divergence in the amplitude of phosphorylation for 4EBP1 (at Thr37/46 and Ser65/Thr70) and p70S6K (Thr389) in response to both Leu and HMB, with the latter showing more pronounced and sustained phosphorylation. … Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. … Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml−1) while continuously infusing AAs (18 g h−1) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008).

^ abcdefghijklmBrioche T, Pagano AF, Py G, Chopard A (August 2016). “Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention”. Molecular Aspects of Medicine. 50: 56–87. doi:10.1016/j.mam.2016.04.006. PMID27106402. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is inexpensive (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people. … 3 g of CaHMB taken three times a day (1 g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013)

^ abcdefghijMolfino A, Gioia G, Rossi Fanelli F, Muscaritoli M (December 2013). “Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials”. Amino Acids. 45 (6): 1273–1292. doi:10.1007/s00726-013-1592-z. PMID24057808. Normally, an individual metabolizes 60 g of L-LEU to obtain 3 g of HMB but a 70 kg person produces 0.2–0.4 g of HMB per day, depending on the dose of LEU in the diet (Van Koevering and Nissen 1992). … The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. … These results show that HMB/ARG/GLN can be safely used to treat AIDS- and cancer-related muscle wasting

^ abcdefgBorack MS, Volpi E (December 2016). “Efficacy and Safety of Leucine Supplementation in the Elderly”. The Journal of Nutrition. 146 (12): 2625S–2629S. doi:10.3945/jn.116.230771. PMC5118760. PMID27934654. One study tested the safety of HMB for long-term use in rats. Fuller et al. (50) conducted a 91-d study with the use of Sprague-Dawley rats that tested the safety of β-hydroxy-β-methylbutyric free acid (HMBFA). This new form of HMB results in higher HMB serum concentrations than CaHMB. In this study, rats were administered an HMBFA intervention of 0%, 0.8%, 1.6%, or 4% of the diet by body weight. The highest dose is the equivalent of ~400 mg ⋅ kg−1 ⋅ d−1 for humans. No adverse advents were observed for any treatment group. Similarly, blood and urine analyses were within the normal range in all groups, with no group differences. The authors concluded that HMBFA was safe for consumption in a rat model. … No serious side effects have been reported with leucine, EAA, or HMB supplementation; and the health risks associated with these supplements are few and predictable.

^ abcdefArgilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (September 2016). “Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease”. Journal of the American Medical Directors Association. 17 (9): 789–796. doi:10.1016/j.jamda.2016.04.019. PMID27324808. Studies suggest dietary protein and leucine or its metabolite β-hydroxy β-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. … These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia. … A growing body of evidence suggests HMB may help slow, or even reverse, the muscle loss experienced in sarcopenia and improve measures of muscle strength. … However, dietary leucine does not provide a large amount of HMB: only a small portion, as little as 5%, of catabolized leucine is metabolized into HMB. … Thus, although dietary leucine itself can lead to a modest stimulation of protein synthesis by producing a small amount of HMB, direct ingestion of HMB more potently affects such signaling, resulting in demonstrable muscle mass accretion. … Indeed, a vast number of studies have found that supplementation of HMB to the diet may reverse some of the muscle loss seen in sarcopenia and in hypercatabolic disease. … The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation. …Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB.

^ abLandi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D’Angelo E, Sisto A, Marzetti E (May 2016). “Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence”. Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC4882708. PMID27187465. HMB is an active leucine metabolite which activates the mTOR signaling pathway in muscle. Following its absorption, dietary leucine is converted into α-ketoisocaproate (KIC), which is further metabolized into either isovaleryl-CoA or HMB. Under normal conditions, the majority of KIC is converted into isovaleryl-CoA, while only approximately 5% of leucine is metabolized to HMB. This implies that, in order to reach pharmacological levels of HMB, this compound needs to be administered directly, rather than via increasing leucine dosage. … HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68].

^ abcdefgMomaya A, Fawal M, Estes R (April 2015). “Performance-enhancing substances in sports: a review of the literature”. Sports Medicine. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID25663250. Currently, HMB is available as an over-the-counter supplement. The drug is not tested for nor banned by any sporting organization. … Wilson et al. [91] demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al. [92] showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. … The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97]. Further, chronic consumption of HMB appears safe [97]. … No serious adverse effects from HMB consumption have been reported.

^ abcdeFuller JC, Sharp RL, Angus HF, Khoo PY, Rathmacher JA (November 2015). “Comparison of availability and plasma clearance rates of β-hydroxy-β-methylbutyrate delivery in the free acid and calcium salt forms”. primary source. The British Journal of Nutrition. 114 (9): 1403–1409. doi:10.1017/S0007114515003050. PMID26373270. Recently, the free acid form of HMB (HMB-FA) has become commercially available in capsule form (gelcap). The current study was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and Ca-HMB. … In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form.

^ abcdefghijklSzcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T (June 2015). “Dietary supplementation of β-hydroxy-β-methylbutyrate in animals – a review”. Journal of Animal Physiology and Animal Nutrition. 99 (3): 405–417. doi:10.1111/jpn.12234. PMID25099672. Cholesterol is a major component of the cell membrane, and sarcolemma is the one that relies mainly on de novo synthesis of cholesterol. This is important under stressful conditions when muscle cells may lack the capacity to produce adequate amounts of the cholesterol that is essential to proper functioning of cell membranes. Many biochemical studies have shown that HMB may be a precursor of cholesterol synthesis (Bachhawat et al., 1955; Bloch et al., 1954; Coon et al., 1955; Adamson and Greenberg, 1955; Gey et al., 1957). According to pertinent literature, HMB carbon is incorporated into cholesterol. Therefore, increased intramuscular HMB concentrations may provide readily available substrate for the cholesterol synthesis that is needed to form and stabilize the sarcolemma. … It is known that HMB supplementation decreases post-exercise levels of enzymes, indicating muscle damage, such as creatinine phosphokinase (CK) and lactate dehydrogenase (LDH), which suggests an enhancement of the muscle cell membrane function. This was shown in numerous studies in humans undergoing both resistance and endurance training (Wilson et al., 2013) … In theory, HMB use as a precursor to cholesterol could aid in stabilizing muscle cell membranes; however, this has not been confirmed by research studies. The effect of HMB on protein metabolism may in fact help stabilize muscle structure more than any effect HMB may have on cholesterol metabolism in the cell.

^ abcCruz-Jentoft AJ (May 2017). “Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to clinical evidence in sarcopenia”. Current Protein & Peptide Science. 18 (7): 668–672. doi:10.2174/1389203718666170529105026. PMID28554316. HMB is widely used as an ergogenic supplement by young athletes. … This study shows that in healthy older adult, HMB supplementation may preserve muscle mass during 10 days of bed rest. These results are encouraging, but need to be confirmed by other groups.

^Mullin GE (February 2014). “Nutrition supplements for athletes: potential application to malnutrition”. Nutrition in Clinical Practice. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID24336486. There are a number of nutrition products on the market that are touted to improve sports performance. HMB appears to be the most promising and to have clinical applications to improve muscle mass and function. Continued research using this nutraceutical to prevent and/or improve malnutrition in the setting of muscle wasting is warranted.

^ abMochamat, Cuhls H, Marinova M, Kaasa S, Stieber C, Conrad R, Radbruch L, Mücke M (July 2016). “A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project”. Journal of Cachexia, Sarcopenia and Muscle. 8 (1): 25–39. doi:10.1002/jcsm.12127. PMC5326814. PMID27897391. Looking at studies with proteins and other dietary supplements the combination of HMB, arginine, and glutamine showed interesting results … In one study, 32 patients gained an average of about 2 kg of body weight.[21] This study was one of three studies confirming the positive effects of this combination in a variety of diagnoses/conditions such as HIV/AIDS patients and healthy adults.[40] Another study, on a far larger sample base of around 470 cancer patients, found no significant difference with regard to LBM after 8 weeks however a strong trend in the direction of an increase in LBM as measured by both bio-impedance and skin-fold measurements.[22] In summary, the effect of the combination of HMB, arginine, and glutamine on weight gain should be investigated in further studies on cancer patients investigating time periods of several months.

^ abRahman A, Wilund K, Fitschen PJ, Jeejeebhoy K, Agarwala R, Drover JW, Mourtzakis M (July 2014). “Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation?”. JPEN. Journal of Parenteral and Enteral Nutrition. 38 (5): 567–575. doi:10.1177/0148607113502545. PMID24072740. More than 20 publications in humans have demonstrated benefit with HMB supplementation associated with increased lean body mass without fat gain, improved markers of muscle strength, and decreased onset of muscle soreness with training and reduced markers of muscle damage. … One proposed cellular mechanism for HMB is principally through stabilization of the cholesterol membrane in muscle cells. HMB is metabolized to β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) in the cytosol of muscle cells, which in turn is converted to cholesterol. … Muscle produces its own cholesterol to maintain the integrity of the cell membrane, typically from HMG-CoA, because it cannot supply its cholesterol needs via absorption from the circulation.

^ abcLuckose F, Pandey MC, Radhakrishna K (2015). “Effects of amino acid derivatives on physical, mental, and physiological activities”. Critical Reviews in Food Science and Nutrition. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID24279396. HMB, a derivative of leucine, prevents muscle damage and increases muscle strength by reducing exercise-induced proteolysis in muscles and also helps in increasing lean body mass. … HMB is converted to HMB-CoA which is then used for the synthesis of cholesterol in muscle cells (Nissen and Abumrad, 1997). Cholesterol is needed for the growth, repair, and stabilization of cellular membranes during exercise (Chen, 1984). … The meta analysis studies and the individual studies conducted support the use of HMB as an effective aid to increase body strength, body composition, and to prevent muscle damage during resistance training.

^ abcRahimi MH, Mohammadi H, Eshaghi H, Askari G, Miraghajani M (2018). “The Effects of Beta-Hydroxy-Beta-Methylbutyrate Supplementation on Recovery Following Exercise-Induced Muscle Damage: A Systematic Review and Meta-Analysis”. Journal of the American College of Nutrition. 37 (7): 640–649. doi:10.1080/07315724.2018.1451789. PMID29676656. The current evidence revealed a time-dependent effect of HMB in reducing LDH and CK serum levels among adults. HMB, therefore, may be seen as a priority muscle damage recovery agent in interventions.

^ ab“Who should not take HMB?”. Metabolic Technologies, Inc. 11 September 2014. Archived from the original on 26 August 2016. Retrieved 23 August 2016. Pregnant or lactating women are advised against taking HMB because safety studies have not yet been conducted for these populations.

^ abcMock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). “Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans”. primary source. The Journal of Nutrition. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC3192457. PMID21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.